부산대학교 도서관

Hepatitis C virus (HCV) causes acute hepatitis C and can lead to life-threating complications if it becomes chronic. The HCV genome is a single plus strand of RNA. Its intracellular replication is a spatiotemporally coordinated process of RNA translation upon cell infection, RNA synthesis within a replication compartment, and virus particle production. While HCV is mainly transmitted via mature infectious virus particles, it has also been suggested that HCV-infected cells can secrete HCV RNA carrying exosomes that can infect cells in a receptor independent manner. In order to gain insight into these two routes of transmission, we developed a series of intracellular HCV replication models that include HCV RNA secretion and/or virus assembly and release. Fitting our models to in vitro data, in which cells were infected with HCV, suggests that initially most secreted HCV RNA derives from intracellular cytosolic plus-strand RNA, but subsequently secreted HCV RNA derives equally from the cytoplasm and the replication compartments. Furthermore, our model fits to the data suggest that the rate of virus assembly and release is limited by host cell resources. Including the effects of direct acting antivirals in our models, we found that in spite of decreasing intracellular HCV RNA and extracellular virus concentration, low level HCV RNA secretion may continue as long as intracellular RNA is available. This may possibly explain the presence of detectable levels of plasma HCV RNA at the end of treatment even in patients that ultimately attain a sustained virologic response. Author summary: Approximately 70 million people are chronically infected with hepatitis C virus (HCV), which if left untreated may lead to cirrhosis and liver cancer. However, modern drug therapy is highly effective and hepatitis C is the first chronic virus infection that can be cured with short-term therapy in almost all infected individuals. The within-host transmission of HCV occurs mainly via infectious virus particles, but experimental studies suggest that there may be additional receptor-independent cell-to-cell transmission by exosomes that carry the HCV genome. In order to understand the intracellular HCV lifecycle and HCV RNA spread, we developed a series of mathematical models that take both exosomal secretion and viral secretion into account. By fitting these models to in vitro data, we found that secretion of both HCV RNA as well as virus probably occurs and that the rate of virus assembly is likely limited by cellular co-factors on which the virus strongly depends for its own replication. Furthermore, our modeling predicted that the parameters governing the processes in the viral lifecycle that are targeted by direct acting antivirals are the most sensitive to perturbations, which may help explain their ability to cure this infection. [ABSTRACT FROM AUTHOR]